We propose to leverage the multicenter international BVMC HHT recruitment network and the BVMC HHT database, in the next funding cycle, to characterize the risk of intracranial hemorrhage (ICH) in HHT patients with BAVMs and subgroups. To do so, we propose to expand the cohort of HHT BAVM patients, building on our established multicenter HHT BAVM database, the largest such cohort in the world. By doubling the cohort size and extending natural history follow-up, in Aim 1 we will increase precision of ICH rates in HHT BAVM patients overall, as well as subgroups of patients, and bring these estimates into a relevant range for clinical decision making. In Aim 2, we propose to investigate genetic modifiers of HHT and BAVM phenotypes, building on preliminary evidence from the first BVMC cycle. We demonstrated that the ALK1 variant IVS3-35A>G is associated with HHT disease severity (presence of any organ AVMs), particularly in patients with an ENG mutation. We therefore postulate a second-hit or trans-heterozygosity hypothesis, which states that in addition to the disease-causing mutation, further reduction of function in the TGFBeta/BMP9 signaling pathway exacerbates HHT phenotypes. To test this hypothesis, we will evaluate common variants in pathway genes for their association with (1) any AVMs and (2) BAVM risk in HHT patients and explore associations with ICH risk and other HHT severity phenotypes. We will utilize the initial BVMC HHT cohort (n=800, 200 BAVM) for discovery and the new second-cycle HHT cohort of 800 for replication. Aim 3 is an exploratory aim, in which we plan to study vessel wall inflammation in BAVMs and ICH, using vessel wall imaging and tissue review for inflammatory cells and mediators. Project 3 participants will be recruited through 12 HHT Centers of Excellence, as well as the Patient Support Organization, HHT Foundation International (HHTFI). The HHT investigator group will continue to work closely with the HHTFI, as well as with the DMCC, leveraging the established DMCC web-based portal, data collection and management protocols in place. The BVMC HHT Project will continue to provide a much-needed and valuable resource for the clinical neurovascular community for the study of BAVMs in HHT.